Risk of COVID-19 death in adults who received booster COVID-19 vaccinations in England

The development and rollout of COVID-19 vaccines significantly reduced severe COVID-19 infections, morbidity, and mortality. However, some groups remained at elevated risk of death even after primary vaccination, and vaccine effectiveness waned over time, necessitating booster doses. In the UK, booster programs prioritized older adults and individuals with specific health conditions. This study aimed to identify groups at increased risk of COVID-19 death after receiving a second booster dose in England's autumn 2022 campaign. Understanding these risks is crucial for informing vaccine prioritization strategies. The study utilized a linked dataset combining 2021 Census data with primary care records and death registration data to estimate the hazard ratio of COVID-19 death for various sociodemographic and clinical risk factors. The researchers also estimated the hazard ratio for non-COVID-19 death to understand the relative risk of COVID-19 death within these groups. The importance of this research lies in its potential to inform the Joint Committee on Vaccination and Immunisation (JCVI) and similar international bodies in their decisions regarding future booster vaccination campaigns, ensuring that the most vulnerable populations receive necessary protection while optimizing resource allocation.

Existing evidence indicates that even after a primary vaccination course and a first booster dose, some individuals remained at elevated risk of COVID-19 hospitalization and death. Studies have shown a decline in vaccine effectiveness over time, highlighting the need for booster doses to maintain protection, particularly as infection control restrictions were eased. While research exists on risk factors following primary vaccination and the first booster, limited evidence addressed risk factors for COVID-19 death after a second booster in autumn 2022. This study fills this gap by investigating the risk factors specifically in this context within the English population.

This retrospective cohort study included 146,514 adults aged 50-100 years who received a second COVID-19 booster dose in England after September 1, 2022. Data were drawn from the 2021 Census, linked to primary care records (GPES data) and death registration data. The primary outcome was COVID-19 death (ICD codes U07.1 and U07.2), and the secondary outcome was all-cause non-COVID-19 death. The study followed participants from 14 days after their booster dose until April 11, 2023. Cox regression models were used to analyze the association between various sociodemographic characteristics (from the Census) and clinical risk factors (from GPES data, based on the QCovid risk prediction model) and the risk of COVID-19 and non-COVID-19 death. Multiple models were fitted, adjusting for age, sex, calendar time, ethnicity, region, and other health conditions. The analysis involved univariate and multivariate models, addressing potential confounders. Missing data were handled using nearest-neighbor donor imputation for Census characteristics and by creating a 'Missing' category for BMI. Due to computational limitations, the analysis was performed on a dataset including all individuals who died and a 5% sample of survivors, weighted appropriately. The analysis was conducted using Spark and R.

Between September 1, 2022, and April 11, 2023, there were 6,800 COVID-19 deaths and 105,607 non-COVID-19 deaths in the study population. Age was a significant predictor for both COVID-19 and non-COVID-19 deaths. Several conditions showed a significantly increased risk of COVID-19 death relative to those without the conditions, including: learning disabilities or Down’s syndrome (HR: 0.57; 95% CI: 0.69–6.98); pulmonary hypertension or fibrosis (HR: 2.85; 95% CI: 2.43–3.40); motor neuron disease, multiple sclerosis, myasthenia gravis, or Huntington’s disease (HR: 2.94; 95% CI: 1.82–4.74); cancer of blood and bone marrow (HR: 2.91; 95% CI: 2.37–3.56); Parkinson’s disease (HR: 2.74; 95% CI: 2.34–3.00); lung cancer, dementia, or liver disease (HR: 2.64; 95% CI: 2.46–2.83); and liver cirrhosis (HR: 2.65; 95% CI: 1.95–3.39). For some conditions (cancer of blood or bone marrow, CKD, cystic fibrosis, pulmonary hypertension or fibrosis, rheumatoid arthritis, or SLE), the relative risk of COVID-19 death was higher compared to non-COVID-19 death. Conversely, for dementia and liver cirrhosis, the risk of non-COVID-19 death was higher. Interestingly, the association between asthma and COVID-19 death varied depending on the model, suggesting that its effect might be confounded by other comorbidities. The study also found that being markedly obese increased the risk of both COVID-19 and non-COVID-19 death, while being underweight was associated with a lower risk of COVID-19 death, but a higher risk of non-COVID-19 death.

This study identifies specific adult populations who remain at increased risk of COVID-19 death even after receiving a second booster dose. The findings highlight the persistent vulnerability of individuals with learning disabilities, neurological conditions, certain cancers, and respiratory or liver diseases. The increased relative risk of COVID-19 death compared to non-COVID-19 death for some conditions underscores the specific impact of COVID-19 on these individuals. The results support previous research showing that, even after boosting, some vulnerable groups remain at heightened risk, although the effectiveness of booster vaccinations in reducing severe outcomes is confirmed. The differences in risk observed between COVID-19 and non-COVID-19 death highlight the specific contribution of COVID-19 in increasing mortality among these individuals above their baseline mortality risk from other causes. The study acknowledges that the findings might not entirely reflect the risk of death since infection but rather the risk of death after receiving the booster. Further research could explore the differential risk of infection and the interplay of pre-existing conditions with post-infection outcomes. The findings strongly support the continued prioritization of these at-risk groups for booster vaccinations, along with the development of targeted therapeutics and treatments.

This study confirms that despite booster vaccinations, certain groups of adults remain at significantly increased risk of COVID-19 death. The specific conditions identified—learning disabilities, various neurological diseases, specific cancers, and respiratory or liver diseases—should be prioritized for future booster campaigns, therapeutic interventions, and further research. The relative risk analysis highlights the specific need for targeted strategies beyond general population-wide vaccination efforts.

The study's retrospective nature and reliance on existing datasets limit the ability to definitively establish causality. The use of administrative data might introduce biases in coding and recording practices that could impact the accuracy of findings. Furthermore, the study focuses on risk of death post-booster vaccination, not post-infection. This limitation prevents a direct evaluation of the risk of infection itself, thus potentially obscuring the full scope of vulnerability. Finally, the reliance on a weighted sample of survivors might introduce some sampling biases.